How to Optimize Goal-Directed Medical Therapy (GDMT) in Patients with Heart Failure.

PURPOSE OF REVIEW: Heart failure is a clinical syndrome with signs and symptoms from underlying cardiac abnormality and evidence of pulmonary or systemic congestion on laboratory testing or other objective findings (Bozkurt et al. in Eur J Heart Fail 23:352-380, 2021). Heart failure with reduced ejection fraction (HFrEF), when heart failure is due to underlying reduction in ejection fraction to ≤ 40. The goal of this review is to briefly describe the mechanisms and benefits of the various pharmacological interventions described in the 2022 AHA/ACC/HFSA Guidelines focusing on Stage C: Symptomatic Heart Failure HFrEF, while providing basic guidance on safe use of these medications. RECENT FINDINGS: Use of medications from each class as recommended in the 2022 Guidelines can provide significant morbidity and mortality benefits for our patients. Despite advances in therapeutics for patients with HFrEF, patients are frequently under treated and more research is needed to help optimize management of these complicated patients.

Technical profiles of child sexual exploitation material offenders.

The idiographic technical profiles of child sexual exploitation material (CSEM) offenders provide insight into their behaviours and context for their interactions with technology, but minimal quantitative work has been done to evaluate their sociability, technical ability and technophilia compared to non-offenders. This work used an online survey to compare an offender group consisting of English-speaking adults previously convicted of CSEM offenses (N = 78) with a reference population of non-offenders (N = 254). The survey assessed sociability, technical ability and technophilia through self-rating and information on occupation, level of education and device ownership. The study found that CSEM offenders had slightly lower sociability than non-offenders, though not at a level of clinical interest. Additionally, CSEM offenders had no statistically significant difference in technical ability and lower overall technophilia when compared to non-offenders. This study fails to support popular perceptions of CSEM offenders being technically savvy loners who are early adopters of new technologies.

The Impact of a Public Health Campaign to Deter Viewing of Child Sexual Abuse Images Online: A Case Study of the UK Stop It Now! Campaign.

Public campaigns offer an opportunity to prevent child sexual abuse by raising awareness and promoting help available to bystanders, victims, and those at risk of perpetrating the abuse. This paper explores the impact of The Lucy Faithfull Foundation's 'Stop It Now!' campaign in the UK (2015-2018) on help-seeking. Helpline calls (11,190 unique callers), website analytics (109,432 new website visitors) and three website-hosted surveys (N = 252) provided data on help-seeking, awareness, and self-reported behavior. Results indicated that there were more visitors to the help website during active campaigning periods, and helpline callers and website visitors were more likely to seek help after viewing campaign materials during active than non-active campaign periods. Help-seekers were predominantly men concerned about their own behavior. Survey 2 respondents concerned about their own behavior (n = 53) indicated that their awareness of the law (75.5%), and legal and personal consequences (67.9%) had changed after hearing about the campaign, and 66% reported a change in behavior. Public health campaigns may be an effective way to promote help-seeking and prevent abuse.

Public Perceptions of Child Pornography and Child Pornography Consumers.

Understanding the public's perceptions of child pornography helps identify gaps in awareness and knowledge, impacts legislative decision making, quantifies stigmatization, and provides a baseline for identifying differences between lay and offender populations for clinical purposes. This research provides a comprehensive public survey assessing these issues. An Internet-based sample of 524 adults (mean age = 47 years, 51% female) within the USA were asked about their understanding and beliefs related to child pornography and individuals who view child pornography. The questions covered three topic areas-general perceptions of child pornography, endorsement of child pornography beliefs, and opinions related to the legality of various forms of child pornography as well as the decision making related to sentencing and sex offender registration for child pornography consumers. The research found that the public viewed these offenses as more severe than most other crimes and that there was an overestimation by the public of risks related to recidivism and contact offending. Additionally, the research found that there was support for most of the current sentencing guidelines in the USA, including sex offender registration, and that there was limited support for treatment over incarceration.

Suicidal ideation in offenders convicted of child sexual exploitation material offences.

Understanding the prevalence of suicidal ideation in Child Sexual Exploitation Material (CSEM) offenders and their psychological concerns provides the basis for early treatment and intervention. This research solicited responses (n = 78) via an anonymous, web-based survey from adults in the United States previously convicted of CSEM offences. Significant suicidal ideation was present in 73% of respondents (n = 57), and 19% (n = 15) reported attempting suicide after they were made aware of an investigation, with 41% (n = 32) stating they would have been likely to seek counselling if provided a contact. Most of the respondents felt they were not treated with fairness, understanding, and compassion by investigators, and that their primary psychological strains were going to jail and their families finding out. This research highlights the need for more empathetic investigative approaches, as well as the need for more rapid assessment and treatment of proximal suicide risk in this population.

Host-parasite interaction associated with major mental illness.

Clinical studies frequently report that patients with major mental illness such as schizophrenia and bipolar disorder have co-morbid physical conditions, suggesting that systemic alterations affecting both brain and peripheral tissues might underlie the disorders. Numerous studies have reported elevated levels of anti-Toxoplasma gondii (T. gondii) antibodies in patients with major mental illnesses, but the underlying mechanism was unclear. Using multidisciplinary epidemiological, cell biological, and gene expression profiling approaches, we report here multiple lines of evidence suggesting that a major mental illness-related susceptibility factor, Disrupted in schizophrenia (DISC1), is involved in host immune responses against T. gondii infection. Specifically, our cell biology and gene expression studies have revealed that DISC1 Leu607Phe variation, which changes DISC1 interaction with activating transcription factor 4 (ATF4), modifies gene expression patterns upon T. gondii infection. Our epidemiological data have also shown that DISC1 607 Phe/Phe genotype was associated with higher T. gondii antibody levels in sera. Although further studies are required, our study provides mechanistic insight into one of the few well-replicated serological observations in major mental illness.

Exploring changes in body image, eating and exercise during the COVID-19 lockdown: A UK survey.

Early reports suggest that lockdown measures associated with the COVID-19 pandemic (e.g., social distancing) are having adverse consequences for people's mental health, including increases in maladaptive eating habits and body dissatisfaction. Certain groups, such as those with pre-existing mental health difficulties, may be especially at risk. The current study explored perceived changes in eating, exercise, and body image during lockdown within the United Kingdom, using an online survey (n = 264). There were large individual differences in perceived changes in eating, exercise, and body image in this period. Women were more likely than men to report increasing struggles with regulating eating, preoccupation with food and worsening body image. Those with a current/past diagnosis of eating disorders reported significantly greater difficulties in regulating eating, increased preoccupation with food, exercise thoughts and behaviours and concern about appearance, even when compared to those with other mental health and developmental disorders. Ongoing research to explore individual differences in the trajectories of change in eating, exercise and body image as lockdown measures ease will be important for understanding the full psychological impact of this pandemic and improve service and public health planning going forward.

A qualitative exploration of the impact of COVID-19 on individuals with eating disorders in the UK.

COVID-19 may have substantial impact on the mental health at a population level, but also has the potential to significantly affect those with pre-existing mental health difficulties such as eating disorders. This qualitative study explores the impact of COVID-19 and associated public health measures on adults with eating disorders within the UK. We conducted 10 in depth interviews with adults (24-38 years) with a self-reported eating disorder during lockdown. Data were analysed using an inductive thematic analysis approach. We identified core themes related to social restrictions (social isolation, changes in accountability to others, and increased responsibility for self and others), functional restrictions (lack of routine and structure, a need to intentionally plan activity, a desire for secrecy particularly around food shopping) and restrictions in access to mental health services. Overall, the impact of the lockdown was experienced as a catalyst for either increased disordered eating behaviours or for a drive for recovery, depending on individual circumstances going into these restrictions. This study is the first in depth interview approach with adults with mixed eating disorder presentations in the UK during COVID-19. Findings have important implications for post lockdown intervention care and practice.

The psychometric properties of Orthorexia Nervosa assessment scales: A systematic review and reliability generalization.

The main objective of this systematic review was to provide a comprehensive overview of the psychometric properties of all available Orthorexia Nervosa (ON) assessment tools, in order to evaluate their scope of application for research and practice. Ten databases were searched for studies quantitatively assessing ON. The psychometric properties were evaluated according to specified quality criteria, focusing on the reliability, structural validity and construct validity of the scales. A meta-analytic approach was used to summarize eligible Cronbach's alpha coefficients between studies. Sixty-eight unique studies fulfilled the inclusion criteria for this systematic review. Ten discrete ON scales were identified. Half of the included studies exclusively utilized a version of the ORTO-15. The evaluation of all available ON measures raise issues regarding ON's dimensionality and conceptualization. Most of the identified scales require further validation. Based on the reported psychometric properties it is advised to re-evaluate existing tools and to focus on establishing consensus regarding the conceptualization of ON to establish a measure with sound psychometric properties.

Plant-based Milks: A Review of the Science Underpinning Their Design, Fabrication, and Performance.

Many consumers are interested in decreasing their consumption of animal products, such as bovine milk, because of health, environmental, and ethical reasons. The food industry is therefore developing a range of plant-based milk alternatives. These milk substitutes should be affordable, convenient, desirable, nutritional, and sustainable. This article reviews our current understanding of the development of plant-based milks. Initially, an overview of the composition, structure, properties, and nutritional profile of conventional bovine milk is given, because the development of successful alternatives depends on understanding the characteristics of real milk. The two main production routes for fabricating plant-based milks are then highlighted: (i) disruption of plant materials (such as nuts, seeds, or legumes) to form aqueous suspensions of oil bodies; (ii) formation of oil-in-water emulsions by homogenization of oil, water, and emulsifiers. The roles of the different functional ingredients in plant-based milks are highlighted, including oils, emulsifiers, thickeners, antioxidants, minerals, and other additives. The physicochemical basis of the appearance, texture, and stability of plant-based milks is covered. The importance of the sensory attributes and gastrointestinal fate of bovine milk and plant-based alternatives is also highlighted. Finally, potential areas for future work are discussed.

Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice.

BACKGROUND: Alcohol use disorders are associated with single-nucleotide polymorphisms in GABRA2, the gene encoding the GABAA receptor α2-subunit in humans. Deficient GABAergic functioning is linked to impulse control disorders, intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear whether α2-containing GABAA receptor sensitivity to endogenous ligands is involved in excessive alcohol drinking. METHODS: Male wild-type (Wt) C57BL/6J and point-mutated mice rendered insensitive to GABAergic modulation by benzodiazepines (BZD; H101R), allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC; Q241M), or high concentrations of ethanol (EtOH) (S270H/L277A) at α2-containing GABAA receptors were assessed for their binge-like, moderate, or escalated chronic drinking using drinking in the dark, continuous access (CA) and intermittent access (IA) to alcohol protocols, respectively. Social approach by mutant and Wt mice in forced alcohol abstinence was compared to approach by EtOH-naïve controls. Social deficits in forced abstinence were treated with allopregnanolone (0, 3.0, 10.0 mg/kg, intraperitoneal [i.p.]) or midazolam (0, 0.56, 1.0 mg/kg, i.p.). RESULTS: Mice with BZD-insensitive α2-containing GABAA receptors (H101R) escalated their binge-like drinking. Mutants harboring the Q241M point substitution in Gabra2 showed blunted chronic intake in the CA and IA protocols. S270H/L277A mutants consumed excessive amounts of alcohol but, unlike wild-types, they did not show forced abstinence-induced social deficits. CONCLUSIONS: These findings suggest a role for: (i) H101 in species-typical binge-like drinking, (ii) Q241 in escalated chronic drinking, and (iii) S270 and/or L277 in the development of forced abstinence-associated social deficits. Clinical findings report reduced BZD-binding sites in the cortex of dependent patients; the present findings suggest a specific role for BZD-sensitive α2-containing receptors. In addition, amino acid residue 241 in Gabra2 is necessary for positive modulation and activation of GABAA receptors by ALLO and THDOC; we postulate that neurosteroid action on α2-containing receptor may be necessary for escalated chronic EtOH intake.

Attentional bias to respiratory- and anxiety-related threat in children with asthma.

This study investigated attentional biases in children with asthma. The study aimed at testing whether children with asthma are vigilant to asthma and/or anxiety cues. Thirty-six children (18 with asthma and 18 healthy controls) aged 9-12 completed a computerised dot probe task designed to measure attentional bias to three different categories of words: asthma, anxiety symptom and general negative emotion. Main caregiver anxiety was also assessed, as was frequency of inhaler use for those with asthma. Children with asthma showed an attentional bias towards asthma words but not anxiety or general negative emotion words. Children without asthma showed no significant attentional biases to any word categories. Caregiver anxiety was correlated with asthma word attentional bias in the asthma group. The findings indicate that attentional bias is present in children with asthma. Further research is required to ascertain if this exacerbates or maintains health-related problems.

The Role of Sexual Images in Online and Offline Sexual Behaviour With Minors.

Sexual images have long been associated with sexual interest and behaviour with minors. The Internet has impacted access to existing content and the ability to create content which can be uploaded and distributed. These images can be used forensically to determine the legality of the behaviour, but importantly for psychiatry, they offer insight into motivation, sexual interest and deviance, the relationship between image content and offline sexual behaviour, and how they might be used in online solicitation and grooming with children and adolescents. Practitioners will need to consider the function that these images may serve, the motivation for their use and the challenges of assessment. This article provides an overview of the literature on the use of illegal images and the parallels with existing paraphilias, such as exhibitionism and voyeurism. The focus is on recent research on the Internet and sexual images of children, including the role that self-taken images by youth may play in the offending process.

An Overview of the Research on Mindfulness-Based Interventions for Treating Symptoms of Posttraumatic Stress Disorder: A Systematic Review.

OBJECTIVE: This systematic review aimed to collate and evaluate the existing research for the use of mindfulness-based approaches to treat posttraumatic stress disorder (PTSD). Our primary objectives were to explore the effects of mindfulness-based approaches on PTSD symptoms and associated psychological distress, with secondary objectives to explore the attrition rate, adverse effects, resource implications, and long-term effects of such interventions. METHOD: We systematically searched research databases, EMBASE, OVID MedLine, Psycinfo, CINAHL, and PILOTS, contacted relevant authors in the field, and conducted a hand search of relevant papers. RESULTS: The search resulted in 12 studies that met eligibility criteria, many of which studies lacked methodological rigor. The majority of the studies indicated positive outcomes with improvements in PTSD symptoms, particularly in reducing avoidance. CONCLUSIONS: The preliminary evidence for the use of mindfulness-based approaches to treat PTSD symptoms is encouraging, although further studies with a more robust research design are required.

Freeze-dried strawberries lower serum cholesterol and lipid peroxidation in adults with abdominal adiposity and elevated serum lipids.

Dietary flavonoid intake, especially berry flavonoids, has been associated with reduced risks of cardiovascular disease (CVD) in large prospective cohorts. Few clinical studies have examined the effects of dietary berries on CVD risk factors. We examined the hypothesis that freeze-dried strawberries (FDS) improve lipid and lipoprotein profiles and lower biomarkers of inflammation and lipid oxidation in adults with abdominal adiposity and elevated serum lipids. In a randomized dose-response controlled trial, 60 volunteers [5 men and 55 women; aged 49 ± 10 y; BMI: 36 ± 5 kg/m(2) (means ± SDs)] were assigned to consume 1 of the following 4 beverages for 12 wk: 1) low-dose FDS (LD-FDS; 25 g/d); 2) low-dose control (LD-C); 3) high-dose FDS (HD-FDS; 50 g/d); and 4) high-dose control (HD-C). Control beverages were matched for calories and total fiber. Blood draws, anthropometrics, blood pressure, and dietary data were collected at screening (0 wk) and after 12-wk intervention. Dose-response analyses revealed significantly greater decreases in serum total and LDL cholesterol and nuclear magnetic resonance (NMR)-derived small LDL particle concentration in HD-FDS [33 ± 6 mg/dL, 28 ± 7 mg/dL, and 301 ± 78 nmol/L, respectively (means ± SEMs)] vs. LD-FDS (-3 ± 11 mg/dL, -3 ± 9 mg/dL, and -28 ± 124 nmol/L, respectively) over 12 wk (0-12 wk; all P < 0.05). Compared with controls, only the decreases in total and LDL cholesterol in HD-FDS remained significant vs. HD-C (0.7 ± 12 and 1.4 ± 9 mg/dL, respectively) over 12 wk (0-12 wk; all P < 0.05). Both doses of strawberries showed a similar decrease in serum malondialdehyde at 12 wk (LD-FDS: 1.3 ± 0.2 µmol/L; HD-FDS: 1.2 ± 0.1 µmol/L) vs. controls (LD-C: 2.1 ± 0.2 µmol/L; HD-C: 2.3 ± 0.2 µmol/L) (P < 0.05). In general, strawberry intervention did not affect any measures of adiposity, blood pressure, glycemia, and serum concentrations of HDL cholesterol and triglycerides, C-reactive protein, and adhesion molecules. Thus, HD-FDS exerted greater effects in lowering serum total and LDL cholesterol and NMR-derived small LDL particles vs. LD-FDS in the 12-wk study. These findings warrant additional investigation in larger trials. This trial was registered at clinicaltrials.gov as NCT01883401.

Serine racemase deletion alters adolescent social behavior and whole-brain cFos activation.

Background: Neurodevelopmental disorders (NDDs) can cause debilitating impairments in social cognition and aberrant functional connectivity in large-scale brain networks, leading to social isolation and diminished everyday functioning. To facilitate the treatment of social impairments, animal models of NDDs that link N- methyl-D-aspartate receptor (NMDAR) hypofunction to social deficits in adulthood have been used. However, understanding the etiology of social impairments in NDDs requires investigating social changes during sensitive windows during development. Methods: We examine social behavior during adolescence using a translational mouse model of NMDAR hypofunction (SR-/-) caused by knocking out serine racemase (SR), the enzyme needed to make D-serine, a key NMDAR coagonist. Species-typical social interactions are maintained through brain-wide neural activation patterns; therefore, we employed whole-brain cFos activity mapping to examine network-level connectivity changes caused by SR deletion. Results: In adolescent SR-/- mice, we observed disinhibited social behavior toward a novel conspecific and rapid social habituation toward familiar social partners. SR-/- mice also spent more time in the open arm of the elevated plus maze which classically points to an anxiolytic behavioral phenotype. These behavioral findings point to a generalized reduction in anxiety-like behavior in both social and non-social contexts in SR-/- mice; importantly, these findings were not associated with diminished working memory. Inter-regional patterns of cFos activation revealed greater connectivity and network density in SR-/- mice compared to controls. Discussion: These results suggest that NMDAR hypofunction - a potential biomarker for NDDs - can lead to generalized behavioral disinhibition in adolescence, potentially arising from disrupted communication between and within salience and default mode networks.

Simple Behavioral Analysis (SimBA) as a platform for explainable machine learning in behavioral neuroscience.

The study of complex behaviors is often challenging when using manual annotation due to the absence of quantifiable behavioral definitions and the subjective nature of behavioral annotation. Integration of supervised machine learning approaches mitigates some of these issues through the inclusion of accessible and explainable model interpretation. To decrease barriers to access, and with an emphasis on accessible model explainability, we developed the open-source Simple Behavioral Analysis (SimBA) platform for behavioral neuroscientists. SimBA introduces several machine learning interpretability tools, including SHapley Additive exPlanation (SHAP) scores, that aid in creating explainable and transparent behavioral classifiers. Here we show how the addition of explainability metrics allows for quantifiable comparisons of aggressive social behavior across research groups and species, reconceptualizing behavior as a sharable reagent and providing an open-source framework. We provide an open-source, graphical user interface (GUI)-driven, well-documented package to facilitate the movement toward improved automation and sharing of behavioral classification tools across laboratories.

Histone serotonylation in dorsal raphe nucleus contributes to stress- and antidepressant-mediated gene expression and behavior.

Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.

Large multimeric assemblies of nucleosome assembly protein and histones revealed by small-angle X-ray scattering and electron microscopy.

The nucleosome assembly protein (NAP) family represents a key group of histone chaperones that are essential for cell viability. Several x-ray structures of NAP1 dimers are available; however, there are currently no structures of this ubiquitous chaperone in complex with histones. We have characterized NAP1 from Xenopus laevis and reveal that it forms discrete multimers with histones H2A/H2B and H3/H4 at a stoichiometry of one NAP dimer to one histone fold dimer. These complexes have been characterized by size exclusion chromatography, analytical ultracentrifugation, multiangle laser light scattering, and small-angle x-ray scattering to reveal their oligomeric assembly states in solution. By employing single-particle cryo-electron microscopy, we visualized these complexes for the first time and show that they form heterogeneous ring-like structures, potentially acting as large scaffolds for histone assembly and exchange.

Imaging material properties of biological samples with a force feedback microscope.

Mechanical properties of biological samples have been imaged with a force feedback microscope. Force, force gradient, and dissipation are measured simultaneously and quantitatively, merely knowing the atomic force microscopy cantilever spring constant. Our first results demonstrate that this robust method provides quantitative high resolution force measurements of the interaction. The small oscillation imposed on the cantilever and the small value of its stiffness result in vibrational energies much smaller than the thermal energy, reducing interaction with the sample to a minimum. We show that the observed mechanical properties of the sample depend on the force applied by the tip and consequently on the sample indentation.